To understand the abnormal behavior of cells in cancer and other human diseases, we must comprehend the basic cellular mechanisms underlying normal cell behavior. One aspect of cellular behavior that is often deregulated in disease is the ability of cells to communicate and cooperate in setting up multi-cellular tissues. The adherens junction initiates assembly of epithelia and organizes a cellular signaling center. Molecular components of this junction have been conserved during evolution, and are key both for normal cell architecture and for certain cell-cell signaling pathways. We have developed a model system to study the role of these proteins in both cell adhesion and signal transduction, using the fruit fly Drosophila melanogaster. This system allows one to combine the sophisticated classical and molecular genetic techniques available in flies with the ability to carry out cell biological and biochemical studies on the same scale as can be carried out in vertebrates. The synergy between vertebrate cell biology and Drosophila developmental genetics is driving much more rapid progress than either approach could yield on its own. The entry point into these studies is the product of the Drosophila armadillo gene, which encodes the structural and functional homolog of the vertebrate adherens junction protein beta-catenin. It is our hypothesis that Armadillo plays key roles both in adherens junction function and in the transduction of the Wingless cell-cell signal, and that specific domains of Armadillo protein and specific protein partners are involved in these different functions. The goals of this proposal are to examine in biochemical detail Armadillo's roles in adherens junction function and in Wg signaling, to examine the possible interdependence of these roles, and to use the Drosophila system to identify and examine the function of other components of the adherens junction complex and the Wingless signal transduction pathway. The specific aims are to: l) Carry out an in vivo structure/function study of Armadillo protein. 2) Dissect Armadillo phosphorylation, and its role in Wingless signaling using a tissue culture model system. 3) Identify and characterize Drosophila homologs of vertebrate APC and p120. 4) Use the yeast two-hybrid system to look for new partners of Armadillo. 3) Use genetic screens to look for new components of the Wingless signaling pathway.